As the most common class of solid tumors, pediatric brain tumors are the leading cause of cancer-related death in children, outpacing all other cancers including leukemias. Low grade gliomas represent the most common pediatric brain tumors and account for more than one third of all newly diagnosed tumors each year. Low grade gliomas that can be completely resected have favorable outcomes. However, children with midline lesions, disseminated low-grade astrocytomas, or low grade tumors that undergo further malignant transfor- mation suffer from significant tumor-related and treatment-related morbidities and have dismal progression-free survival. Recently, unifying genomic alterations in MAPK signaling have been found to typify this class of tu- mors, opening new potential avenues for directed, targeted therapies for affected children. Through cell-based, genomic, and animal model systems, this proposal addresses the molecular mechanisms of susceptibility, tar- geting, and the associated mechanism(s) of resistance to novel therapies in various subtypes and histopathol- ogies of BRAF-altered pediatric low grade brain tumors. Specifically, the proposal expands on preliminary data utilizing pharmacological inhibitors that define unique molecular mechanisms of resistance and an associated MAPK pathway paradoxical activation in the setting of mutant, BRAF-fusion gene expression. The proposed research also builds on whole genome sequencing efforts and an initial investigation of second-generation BRAF inhibitors and defines new avenues and model systems for identifying collaborating mutations that drive distinct BRAF-altered central nervous system malignancies. Together the aims of the proposed research will provide mutations-specific therapeutic opportunities for low grade gliomas and further define the underlying biology of this class of tumors.